Global gene expression and functional network analysis of gastric cancer identify extended pathway maps and GPRC5A as a potential biomarker.

To get more understanding of the molecular mechanisms underlying gastric cancer, 25 paired samples were applied to gene expression microarray analysis. Here, expression microarray, quantitative reverse transcription-PCR (qRT-PCR) and immunohistochemical analysis indicated that GPRC5A was significantly elevated in gastric cancer tissues. The integrative network analysis of deregulated genes generated eight subnetworks. We also mapped copy number variations (CNVs) and associated mRNA expression changes into pathways and identified WNT, RTK-Ras-PI3K-AKT, NF-κB, and PLAU-JAK-STAT pathways involved in proliferation, evading apoptosis and sustained angiogenesis, respectively. Taken together, our results reveal several interesting genes including GPRC5A as potential biomarkers for gastric cancer, and highlight more systematical insight of deregulated genes in genetic pathways of gastric carcinogenesis.

[1]  Tsviya Olender,et al.  GeneCards Version 3: the human gene integrator , 2010, Database J. Biol. Databases Curation.

[2]  Yusuke Nakamura,et al.  Genetic variation in PSCA is associated with susceptibility to diffuse-type gastric cancer , 2008, Nature Genetics.

[3]  Z. Ye,et al.  SPARC Is Associated with Gastric Cancer Progression and Poor Survival of Patients , 2009, Clinical Cancer Research.

[4]  King-Jen Chang,et al.  Gene expression profile predicts patient survival of gastric cancer after surgical resection. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[5]  R. Lotan,et al.  A Gprc5a tumor suppressor loss of expression signature is conserved, prevalent, and associated with survival in human lung adenocarcinomas. , 2010, Neoplasia.

[6]  Seung Woo Park,et al.  Up-regulated claudin 7 expression in intestinal-type gastric carcinoma. , 2007, Oncology reports.

[7]  G. Şimşek,et al.  Comparison of the desmoplastic reaction and invading ability in invasive ductal carcinoma of the breast and prostatic adenocarcinoma based on the expression of heat shock protein 47 and fascin. , 2010, Analytical and quantitative cytology and histology.

[8]  Antoine M. van Oijen,et al.  Real-time single-molecule observation of rolling-circle DNA replication , 2009, Nucleic acids research.

[9]  W. Liang,et al.  9) TM4 Microarray Software Suite , 2006 .

[10]  Q. Fan,et al.  miR-137 Is Frequently Down-Regulated in Gastric Cancer and Is a Negative Regulator of Cdc42 , 2011, Digestive Diseases and Sciences.

[11]  Qiwei Yang,et al.  Methylation-Associated Silencing of the Heat Shock Protein 47 Gene in Human Neuroblastoma , 2004, Cancer Research.

[12]  J. Gu,et al.  Prostate Stem Cell Antigen: A Jekyll and Hyde Molecule? , 2010, Clinical Cancer Research.

[13]  M. Emi,et al.  Identification of RAI3 as a therapeutic target for breast cancer. , 2005, Endocrine-related cancer.

[14]  G. Serio,et al.  Gene expression analysis of early and advanced gastric cancers , 2007, Oncogene.

[15]  Hongbing Shen,et al.  Genetic variation of PSCA gene is associated with the risk of both diffuse‐ and intestinal‐type gastric cancer in a Chinese population , 2010, International journal of cancer.

[16]  S. S. Koh,et al.  Claudin-4 overexpression is associated with epigenetic derepression in gastric carcinoma , 2011, Laboratory Investigation.

[17]  Jun Xia,et al.  Upregulated INHBA expression is associated with poor survival in gastric cancer , 2012, Medical Oncology.

[18]  I. Okayasu,et al.  High expression of HSP47 in ulcerative colitis-associated carcinomas: proteomic approach , 2009, British Journal of Cancer.

[19]  Yan Zhou,et al.  Genetic variant in PSCA predicts survival of diffuse‐type gastric cancer in a Chinese population , 2011, International journal of cancer.

[20]  H. Xiao,et al.  Upregulated expression of S100A6 in human gastric cancer , 2007, Journal of digestive diseases.

[21]  W. Ahn,et al.  An 8-gene signature, including methylated and down-regulated glutathione peroxidase 3, of gastric cancer. , 2009, International journal of oncology.

[22]  Gary D. Bader,et al.  Pathway Commons, a web resource for biological pathway data , 2010, Nucleic Acids Res..

[23]  Y. Doki,et al.  Integrative approach for differentially overexpressed genes in gastric cancer by combining large-scale gene expression profiling and network analysis , 2008, British Journal of Cancer.

[24]  Khean Lee Goh,et al.  Screening for gastric cancer in Asia: current evidence and practice. , 2008, The Lancet. Oncology.

[25]  Brad T. Sherman,et al.  Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources , 2008, Nature Protocols.

[26]  Kathryn A. O’Donnell,et al.  An integrated database of genes responsive to the Myc oncogenic transcription factor: identification of direct genomic targets , 2003, Genome Biology.

[27]  A. Jemal,et al.  Global Cancer Statistics , 2011 .

[28]  Brad T. Sherman,et al.  Bioinformatics enrichment tools: paths toward the comprehensive functional analysis of large gene lists , 2008, Nucleic acids research.

[29]  Setsuo Hirohashi,et al.  CXCL17 and ICAM2 are associated with a potential anti-tumor immune response in early intraepithelial stages of human pancreatic carcinogenesis. , 2011, Gastroenterology.

[30]  Kyle J Hewitt,et al.  The claudin gene family: expression in normal and neoplastic tissues , 2006, BMC Cancer.

[31]  Chi V. Dang,et al.  c-Myc Target Genes Involved in Cell Growth, Apoptosis, and Metabolism , 1999, Molecular and Cellular Biology.

[32]  Wen-Chi Chou,et al.  An integrated transcriptomic and computational analysis for biomarker identification in gastric cancer , 2010, Nucleic acids research.

[33]  J. Cameron,et al.  Immunohistochemical validation of a novel epithelial and a novel stromal marker of pancreatic ductal adenocarcinoma identified by global expression microarrays: sea urchin fascin homolog and heat shock protein 47. , 2002, American journal of clinical pathology.

[34]  Young-Joon Kim,et al.  Expression patterns of aurora kinase B, heat shock protein 47, and periostin in esophageal squamous cell carcinoma. , 2009, Oncology Research.

[35]  Koichi Hirata,et al.  Gene expression analysis identifies over‐expression of CXCL1, SPARC, SPP1, and SULF1 in gastric cancer , 2010, Genes, chromosomes & cancer.

[36]  E. Prochownik,et al.  MYC oncogenes and human neoplastic disease , 1999, Oncogene.

[37]  Alessandro Ambrosi,et al.  Gene Expression Profile of Primary Gastric Cancer: Towards the Prediction of Lymph Node Status , 2007, Annals of Surgical Oncology.

[38]  Ming Li,et al.  Overexpression of VCC-1 gene in human hepatocellular carcinoma cells promotes cell proliferation and invasion. , 2009, Acta biochimica et biophysica Sinica.

[39]  Hermann Brenner,et al.  Epidemiology of stomach cancer. , 2009, Methods in molecular biology.

[40]  S. Knuutila,et al.  Integrated gene copy number and expression microarray analysis of gastric cancer highlights potential target genes , 2008, International journal of cancer.

[41]  G. Rosenberger,et al.  The MYC dualism in growth and death. , 1999, Mutation research.

[42]  R. Mazzarella,et al.  VCC-1, a novel chemokine, promotes tumor growth. , 2006, Biochemical and biophysical research communications.

[43]  Nils Brünner,et al.  The Plasminogen Activator Inhibitor PAI-1 Controls in Vivo Tumor Vascularization by Interaction with Proteases, Not Vitronectin , 2001, The Journal of cell biology.

[44]  Kathryn A. O’Donnell,et al.  The c-Myc target gene network. , 2006, Seminars in cancer biology.

[45]  A. Kaneda,et al.  Decreased expression of the seven ARP2/3 complex genes in human gastric cancers. , 2004, Cancer letters.

[46]  Lei Qiao,et al.  Genetic variations of prostate stem cell antigen (PSCA) contribute to the risk of gastric cancer for Eastern Asians: a meta-analysis based on 16792 individuals. , 2012, Gene.

[47]  E. Dahl,et al.  Production and characterisation of monoclonal antibodies against RAI3 and its expression in human breast cancer , 2009, BMC Cancer.

[48]  Ping Wang,et al.  Identification of genes with a correlation between copy number and expression in gastric cancer , 2012, BMC Medical Genomics.

[49]  Alex E. Lash,et al.  Gene Expression Omnibus: NCBI gene expression and hybridization array data repository , 2002, Nucleic Acids Res..

[50]  R. Lotan,et al.  Identification of the Retinoic Acid – Inducible Gprc5a as a New Lung Tumor Suppressor Gene , 2022 .

[51]  Susumu Goto,et al.  KEGG for representation and analysis of molecular networks involving diseases and drugs , 2009, Nucleic Acids Res..

[52]  L. Montaño,et al.  Distribution and Expression Pattern of Claudins 6, 7, and 9 in Diffuse- and Intestinal-Type Gastric Adenocarcinomas , 2010, Journal of gastrointestinal cancer.

[53]  Masahiko Watanabe,et al.  Immunohistochemical distribution of heat shock protein 47 (HSP47) in scirrhous carcinoma of the stomach. , 2006, Anticancer research.

[54]  Hyun Cheol Chung,et al.  Oncogenic Pathway Combinations Predict Clinical Prognosis in Gastric Cancer , 2009, PLoS genetics.

[55]  C. Moskaluk,et al.  Expression of tight-junction protein claudin-7 is an early event in gastric tumorigenesis. , 2005, The American journal of pathology.